A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF
Tekijät: Michaëlsson Erik, Lund Lars H., Hage Camilla, Shah Sanjiv .J., Voors Adriaan .A., Saraste Antti., Redfors Björn., Grove Erik .L., Barasa Anders., Richards A.Mark., Svedlund Sara., Lagerström-Fermér Maria., Gabrielsen Anders., Garkaviy Pavlo, Gan Li-Ming, Lam Carylon S.P.
Kustantaja: Elsevier Inc.
Julkaisuvuosi: 2023
Journal: JACC: Heart Failure
Tietokannassa oleva lehden nimi: JACC: Heart Failure
Vuosikerta: 11
Numero: 7
Aloitussivu: 775
Lopetussivu: 787
ISSN: 2213-1779
DOI: https://doi.org/10.1016/j.jchf.2023.03.002
Verkko-osoite: https://doi.org/10.1016/j.jchf.2023.03.002
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/180235896
Background: Systemic microvascular dysfunction and inflammation are postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF).
Objectives: This study aimed to identify biomarker profiles associated with clinical outcomes in HFpEF and investigate how inhibition of the neutrophil-derived reactive oxygen species-producing enzyme, myeloperoxidase, affects these biomarkers.
Methods: Using supervised principal component analyses, the investigators assessed the associations between baseline plasma proteomic Olink biomarkers and clinical outcomes in 3 independent observational HFpEF cohorts (n = 86, n = 216, and n = 242). These profiles were then compared with the biomarker profiles discriminating patients treated with active drug vs placebo in SATELLITE (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure), a double-blind randomized 3-month trial evaluating safety and tolerability of the myeloperoxidase inhibitor AZD4831 in HFpEF (n = 41). Pathophysiological pathways were inferred from the biomarker profiles by interrogation of the Ingenuity Knowledge Database.
Results: TNF-R1, TRAIL-R2, GDF15, U-PAR, and ADM were the top individual biomarkers associated with heart failure hospitalization or death, and FABP4, HGF, RARRES2, CSTB, and FGF23 were associated with lower functional capacity and poorer quality of life. AZD4831 downregulated many markers (most significantly CDCP1, PRELP, CX3CL1, LIFR, VSIG2). There was remarkable consistency among pathways associated with clinical outcomes in the observational HFpEF cohorts, the top canonical pathways being associated with tumor microenvironments, wound healing signaling, and cardiac hypertrophy signaling. These pathways were predicted to be downregulated in AZD4831 relative to placebo-treated patients.
Conclusions: Biomarker pathways that were most strongly associated with clinical outcomes were also the ones reduced by AZD4831. These results support the further investigation of myeloperoxidase inhibition in HFpEF.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
